The goals of this project are as follows: identify the mechanisms underlying the effects of gonadal steroids on the regulation of affective state; identify the effects of aging, reproductive senescence, and gender on the neuroregulatory actions of gonadal steroids; determine the therapeutic utility of hormonal therapies (i.e., gonadal steroids and adrenal androgens) in mood disorders occurring during midlife and the perimenopause; and identify the predictors of antidepressant response to hormone therapy in reproductive endocrine-related mood disorders. Findings to date include: 1) significant improvement in measures of depression severity scores and verbal memory performance (but not libido) after estrogen replacement in women with perimenopausal depression independent of estrogen's salutary effects on vasomotor symptoms; 2) the recurrence of depressive symptoms after the administration of the serotonin agent metergoline but not placebo in seven depressed perimenopausal women who responded to estrogen replacement under placebo-controlled conditions; 3) significant improvement in depression severity scores (but not measures of cognitive function or libido) after DHEA administration in 18 men and 18 women with midlife-related depression; 4) significant increases in plasma levels of the testosterone metabolite and putative neurosteroid androsterone after DHEA administration in men; and 5) no significant effects of DHEA on vascular motility, or plasma and urinary markers of bone metabolism. In a study involving the induction of hypogonadism in men and women with GnRH agonists, we have observed the hypogonadal state to be associated with the following: 1) decreased measures of sexual function in both men and women, with a restoration of normal sexual function during gonadal steroid replacement in 20 men with testosterone but not in 20 women with either estradiol or progesterone; 2) no significant effects on measures of cognitive function in either women or men (in contrast to estradiol-related improvement in verbal memory observed in the older perimenopausal women); 3) no significant effects on mood and behavioral symptoms in men (with the exception of libido and hot flushes); 4) elimination of cognition activated regional cerebral blood flow (O15 PET scans) in the dorsolateral prefrontal cortex in women but not men and preliminary evidence of a similar pattern of cognition activated r-CBF employing different cognitive activation paradigms and using 3D PET and FMRI techniques (preliminary results in six women show a significant effect of hormone condition during the two back working memory task on left hippocampal activation, with estradiol activating and progesterone inhibiting activation compared with the hypgonadal state); 5) decreased cerebral spinal fluid (CSF) measures of testosterone (T), dihydrotestosterone, and androsterone (relative to T replacement) but no gonadal steroid-related differences in CSF measures of monoamine metabolites in men; and 6) decreased ACTH, cortisol, and AVP secretion after exercise (compared to progesterone replaced conditions) with no differences following ovine CRH tests in women, and increased cortisol and decreased ACTH secretion but no effects on AVP secretion (compared to testosterone replaced conditions) during CRH or exercise stimulation in men. Additionally, we have observed sexual dimorphisms during the hypogonadal state (i.e. gender differences that are independent of the presence of gonadal steroids) in several measures: m-CPP stimulated growth hormone secretion (increased in women); spatial ability (increased in men). Finally, we have initiated collaborative investigations with the NICHD to examine the effects of T replacement on mood and behavior in women with Turner's Syndrome and in women with premature ovarian failure.